Associate Professor

Research Interest

Despite groundbreaking work in defining the genetic and epigenetic basis for cancer, hypertension, type-2 diabetes, neurodegenerative disorders, and other clinical conditions; therapies still remain palliative. I amd attempting to develop an innovative approach to treat underlying epigenetic defects (promoter DNA methylation/demethylation) common to these disorders. Several studies have demonstrated significant changes in DNA methylation, which switches DNA between Hetrochromatin and Euchromatin, an important factor in the pathogenesis of these disorders. Furthermore, hypermethylation of Angiotensin Converting Enzyme, BRACA1, p53, and hypomethylation of c-myc, ras, and other genes involved in these disorders, provide rationale to devise therapies that targets DNA methylation. During the past several decades, attempts have been made to target DNA methylation by pharmacological agents such as 5-aza-2'-deoxycytidine, arabinofuranosyl-5-azacytosine, MG-98 and others. Cell/Gene specificity provides the single greatest challenge, however. We have developed an innovative approach to overcome this. The potential to translate these approaches to the bedside, is a the major strategic plan. We start with identifying the alterations in promoter DNA methylation with diseases. Then with novel zinc finger proteins, which can recognize specific DNA sequences, we are conducting experiments to fuse methylase or demethylase enzymes, and attempt to change methylation in a desired direction, in both cell culture and animal models, to achieve the promise of gene therapy. The approaches are not limited to the diseases mentioned above; they will be beneficial in future research in many ways. For instance, it will help to fulfill the dream of stem cell therapy by directing cellular differentiation, generating epigenetic transgenic mice strains by selectively targeting, at the embryonic stage, promoter DNA methylation of a single gene at specific CpG Island. Importantly, the ability to selectively modify promoter DNA methylation, as a therapy in vivo, could revolutionize the treatment of diverse genetic diseases, and fulfill the therapeutic promise of the Human Genome Project.

The second project is to elucidate the mechanisms involved in long-term hypoxia acclimatization. As widely accepted, in response to hypoxia exposure, hypoxia inducible factor 1α (HIF1α) plays a crucial role in cell survival. Notably, with long-term hypoxia exposure HIF1α levels returns to the basal level. Mechanisms are not known, however. Moreover, silencing of HIF1α in the acute phase of hypoxia abolishes the long-term hypoxia-induced up-regulation of a number of genes. Thus, HIF1α appears to be crucial in long-term regulation of these genes, despite its return to the basal level with continued hypoxia. This may be possible through epigenetic modifications of the DNA by HIF1α. Thus, to elucidate HIF1α-mediated long-term gene regulation and to gain mechanistic insights, we are currently examining HIF1α induced transcriptional epigenetic changes and cellular adaptive responses. Furthermore, our studies demonstrate post-translational phosphorylation of ERK with chronic hypoxia. In the current studies we are conducting experiment to test the hypothesis that hypoxia exposure leads to HIF1α-mediated changes in the gene expression by transcriptional epigenetic regulation. We also are working on the associated hypothesis that retrograde mitochondrial signaling is involved in the constitute ERK phosphorylation.